PROJECT 3: Control of Leukocyte Emigration in Reperfused Myocardium Project 3 focuses its long term objective on the mechanisms by which neutrophils and monocytes emigrate into inflammatory sites and interact with parenchymal cells. The project has developed a number of in vitro experimental models of identification The project has developed The project has developed a number of in vitro experimental models for identification of mechanisms that may operate in the reperfused myocardium. These specific adhesion molecules, and the changes in functions that occur in response to local cytokines and chemokines. This general approach will continue in the present application There are two specific aims for this project with immediate and focused sub-aims under each that are linked to condition or factors known to be present in the reperfused myocardium. They are chosen to fill gaps in our understanding of the mechanisms that control leukocyte emigration and function in the heart. Specific Aim 1- Define new steps in the leukocyte adhesion and signaling cascade operate in reperfused myocardium. The specific focus of this aim will be in four areas; a) alterations in leukocyte functions induced by the selectin family of adhesion molecules that tether leukocytes to endothelial cells under conditions of shear by flowing blood; b) the broad functions in neutrophils of LFA-1, a member of the CD18 integrin family; c) the leukocyte functions supported by myocardial ICAM-1 (a ligand for CD18 integrins) in contrast to ICAM-1 on peripheral venules; and d) the functional contributions of oncostatin M and IL-15 in myocardium as they apply to the adhesion and signaling cascade. Specific Aim 2- Define anti-adhesive mechanisms that modulate the leukocyte adhesion and signaling cascade in reperfused myocardium. The specific focus of this aim will be in 3 areas; a) the anti-adhesive properties of combined cytokine stimulation using IL-1 and IL-4 as a model; b) the potential role of anti-inflammatory cytokines up-regulated in the myocardium by reperfusion, with focus on IL-10; and c) the potential contributions of soluble myocardial-derived adhesion molecules, especially ICAM-1.